THE INSTITUTE OF ONCOLOGY, LJUBLJANA FIVE-YEAR SURVIVAL OF PATIENTS WITH BREAST CANCER ANO AXILLARY LYMPH NOOE METASTASES TREATEO BY POSTOPERATIVE IRRAOIATION ANO AOJUVANT CHEMOTHERAPY Stabuc B, Plesnicar S Abstract — Five-year survival of patients with operable breast cancer and metastases in the axillary lymph nodes was studied. Following modified radical mastectomy (Maden-Patey), the patients were treated either by postoperative irradiation or adjuvant chemotherapy according to CMF schedule. In 169 patients treated by adjuvant chemotherapy the 5-year survival was found to be 72 %, whereas in 126 patients receiving postoperative irradiation it was 60% (p = 0.04). Five-year survival in patients without evidence of disease (NED) treated by adjuvant chemotherapy was 61 %, and in irradiated patients 50 % (p = 0.02). Statistically significant better survival of patients receiving adjuvant chemotherapy (p < 0.05) was found only in those with tumors smaller than 2 cm, and less than 3 or less than 7 positive axillary lymph nodes, respectively. UDC: 616.19-006.6-089:616.428-0332-085 Key words: breast neoplasms-surgery, lymphatic metastasis, radiotherapy, antineoplastic agents, prognosis Orig. sci. paper Radiol lugosl 1989; 23: 177-82. lntroduction — In Europe, North America and also in our country breast cancer still represents the most common form of cancer in women. According to the data of the Cancer Registry of Slovenia tor the year 1984, there were 612 newly detected breast cancer patients in Slovenia. The incidence per 100 000 women was 51.2 (1). Surgery still remains the treatment of choice in patients with operable breast cancer. Ten-year survival in patients with operable breast cancer treated by radical or modified radical mastectomy ranges from 50 % to 60 % (2, 3). The surgical treatment was combined with postoperative irradiation with the intent to eliminate possible micrometastases in the thoracic wall and regional lymph nodes, and thus cure the patient. Nevertheless, in spite of several studies, the relevance of postoperative irradiation has not been fully explained. Most authors report no significant improvement in the survival of patients treated by postoperative irradiation despite a smaller number of local recurrences (4, 5). According to Montague (6), postoperative irradiation may result in a prolonged survival in individual patients with operable breast cancer and metastases in the axillary lymph nodes. At the Institute of Oncology in Ljubljana, the survival of patients with operable breast cancer treated by radical mastectomy and postoperative irradiation was not found to be longer than that in patients treated by radical mastectomy alone (7). Most patients with operable breast cancer die from metastases and not from local recurrence despite the radical local treatment. This finding supports the hypothesis that cancer is not a local, but rather a systemic disease. Therefore, patients after mastectomy require an additional systemic treatment (8, 9). The studies carried out by the end of 70's and the beginning of 80's showed that adjuvant systemic treatment resulted in an improved survival and disease-free survival in individual patients with operable breast cancer only (10, 11, 12, 13). The aim of the present study was to establish possible differences in the survival of patients with operable breast cancer: treated by postoperative irradiation or adjuvant chemotherapy. Patients and methods — The study comprised the patients with operable breast cancer and axillary lymph node metastases (Ti-T3aNi--NibMo), treated at the Institute of Oncology in Ljubljana by postoperative irradiation or adjuvant chemotherapy according to CMF schedule following radical or modified radical mastec- Received: August 17, 1987 — Accepted: September 1, 1987 110 Stabuc B., et al.: Five-year survival of patients with breast cancer and axillary lymph node metastases treated by postoperative irradiation and .. tomy. In the group with postoperative irradiation there were 126 patients, of these 38 (30 %) were irradiated on an ortovoltage X-ray machine with the energy of 180 Kv to the five fields as follows: parasternally, two tangent fields onto the thoracic wall, supraclavicular and axillary fields. The irradiation was performed in two courses, the daily dose being 250 r. Skin dose after the completed first course amounted to 10950 r, and after the second 9750 r. Another 88 (70 %) patients were irradiated with Cobalt to the following three fields: parasternal, supraclavicular and axillary. Tumor dose was 4400 cGy, and daily dose 200 cGy. Postoperative adjuvant chemotherapy according to the CMF schedule was applied in 169 patients Cyclophosphamide 100 mg/m2 1-14 days per os; MTX 40 mg/m2 i. v. on day 1 and 8; 5-FU 600 mg/m2 on day 1 and 8 i .v.). The chemotherapy cycle was repeated 12 times, every 4 weeks. Only the patients with pathohisto-logically verified axillary lymph node metastases were included. Metastases before mastectomy were exluded by clinical. laboratory, X-ray and radionuclide examinations. All the patients with advanced breast cancer (T3b-T4NrN3Mi), and those with negative axillary lymph nodes, as well as the patients receiving either irradiation, chemo- or immunotherapy prior to mastectomy, the patients postoperatively treated by irradiation and chemotherapy, and the patients entering for adjuvant therapy after the 42nd postoperative day were excluded from the study. The follow up was 60 months after mastectomy. Statistic significance in the 5-year survival and 5-year survival without evidence of disease in patients treated either by adjuvant chemotherapy or postoperative irradiation was calculated using log-rank test (14). The life-table method was used for graphic analysis. Results — The characteristics of patients with operable breast cancer and metastases in the axillary lymph nodes are presented in Table 1. The were 169 patients treated by adjuvant chemotherapy (ChT) and 126 by postoperative irradiation (RT). Both groups were correlated by age, tumor size, menstural status, number of positive axillary lymph nodes, hormone receptors and malignancy grade. Patients with adj uvant chemotherapy had statistically significantly longer 5-year survival than those treated by postoperative irradiation (ChT 72 ± 3 %; RT 60 ± 4 %; p = 0.04) (Table 2, Fig. 1). AII % ChT % RT % Patients 295 % 169 57% 126 43% Age <40 56 19% 35 21% 21 43% 40-49 111 38% 68 40% 43 34% >50 128 43% 66 39% 62 49% Tumor size 65 22% 39 23% 26 21% >2 230 78% 130 77% 100 79% Menopause premenopausal 175 - 59% 115 67% 60 48% postmenopausal 93 31% 40 25% 53 42% perimenopausal 27 10% 14 8% 13 10% Lymph nodes 153 52% 85 50% 68 54% >3 142 48% 84 50% 58 46% Hormone receptors HR+ 72 25% 64 38% 8 6% HR- 65 22% 57 34% 8 6% HRn 158 53% 48 28% 11O 88% Malignancy grade 221 138 83 1 19 9% 12 9% 7 8% II 146 66% 96 69% 50 61% III 56 25% 30 22% 26 31% Table 1 - Characteristics of patients with operable breast cancer and axillary lymph node metastases treated by adjuvant chemotherapy (ChT) and postoperative irradiation (RT) 182 Radiol lugosl 1989: 23: 177-82 Stabuc B., et al.: Five-year survival of patients with breast cancer and axillary lymph node metastases treated by postoperative irradiation and. Patients AII % Dead Alive %±SD p ChT 169 57% 48 121 72%±3 RT 126 43% 50 76 60%±4 0.04 Total 295 98 197 Table 2 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases treated either by ChT or RT Five-year survival without evidence of disease was statistically significantly better in patients receiving adjuvant chemotherapy than in those treated by postoperative irradiation (ChT 61±4 %; RT 50 ± 4 %; p = 0.02) (Table 3, Fig. 2). Patients with adjuvant chemotherapy were distributed into subgroups according to tumor size, number of positive axillary lymph nodes, malignancy grade, tumor size in the breast, hormone receptor, menopausal status and age. Statistically significant differences in the 5-year survival (p < O.OS) were established only in patients with tumors smaller than 2 cm (ChT 92±4%; RT 54±10%; p = 0.001) (Table 4) and 1.0 I ----KT _RT 12 36 month 48 60 Fig. 1 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases treated either by ChT or RT Patients AII % Recurrence NED %±SD p ChT 169 57% 66 103 61 %±4 RT 126 43% 63 63 50%±4 0.02 Total 295 129 166 Table 3 — Five-year survival without evidence of disease in patients with operable breast cancer and axillary lymph node metastases treated either by ChT or RT in patients with less than 3 positive axillary lymph nodes (ChT 86±4%; RT 75±5%; p = 0,05) (Table 5). Sixty five patients had tumor measuring 2 cm or less. There were 39 patients (60 %) treated by adjuvant ChT and 26 (40%) by postoperative irradiation (ChT 82±6%; RT 50±10%; p = 0.004) (Fig. 3). Less than 3 positive axillary lymph nodes were found in 85 (56 %) patients with adjuvant chemotherapy, and 68 (44%) patients with postoperative irradiation (ChT 82±4%; RT 65±6%; p = 0.01) (Fig. 4). Also the patients with less than 8 positive axillary lymph nodes treated by adjuvant chemothe- 1.0 12 24 36 month 48 60 Fig. 2 — Five-year survival without evidence of disease in patients with operable breast cancer and axillary lymph node metastases treated either by ChT or RT Radiol lugosl 1989; 23: 177-82 179 . 5 Stabuc B., et al.: Five-year survival of patients with breast cancer and axillary lymph node metastases treated by postoperative irradiation and .. Tumor size AII % Dead Alive % + SD P Tumor 2 cm 615 115 50 ChT 319 60% 3 3(3 92%± 4 0.001 RT 2(3 40% 112 1-4 54%±10 Tumor 3—"4 cm 163 58 105 ChT 9(3 59% 31 35 68%± 5 0.2 RT 6-7 41% 2 7 40 60%± 6 Tumor 4 cm 67 25 42 ChT 34 51 % 14 20 59%± 8 0.4 RT 33 49% 11 22 67%± 8 Table 4 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases treated either by ChT or RT according to tumor size 1.0 ,5 KT RT 12 24 36 48 month 1. O ■1_____ KT RT 60 24 36 month 5 60 12 Fig. 3 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases without evidence of disease, treated either by ChT or RT, with tumors smaller than 2 cm. Fig. 4 — Five-year survial in patients with operable breast cancer and axillary lymphn node metastases without evidence of disease, treated either by ChT or RT, with less than 3 involved lymph nodes. No. of l.n. AII % Dead Alive %±SD p 3 lymph n. 153 29 124 ChT 85 53% 112 73 68% + 4 O.OS RT 68 44% 17 51 75%±5 4—7 lymph n. 68 30 3(3 ChT 39 57% 14 25 64% + 8 0.1 RT 29 43% 16 13 45%±9 8 lymph n. 74 39 35 ChT 45 31 % 22 23 51 %±7 0.4 RT 29 319% 17 112 41 % + 9 Table 5 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases treated by ChT or RT, according to the number of involved axillary lymph nodes rapy had longer 5-year survival without evidence of disease than those treated by postoperative irradiation (ChT 54 ± 8 %; RT 31 ± 9 %; p = 0.04). Patients with tumor in the lateral quadrant of the breast, treated by ChT, had longer survival than those treated by RT (ChT 58 ± 5 %; RT 46 ± 5 %; p = 0.04) (Table 6). Discussion — The patients treated by adjuvant chemotherapy were found to have longer 5-year survival and 5-year survival without evidence of disease than those treated by postoperative irradiation. Considering the prognostic factors, statistically significant differences were found only in patients with tumors smaller than 2 cm, or in those with less than 3 or 7 affected lymph nodes. 182 Radiol lugosl 1989: 23: 177-82 Stabuc B., et al.: Five-year survival of patients with breast cancer and axillary lymph node metastases treated by postoperative irradiation and. Tumor site AII % Recurrence NED %±S0 P Lateral quadrant 194 92 102 ChT 105 54% 44 61 58%± 5 0 04 RT 89 40% 48 41 46%± 5 0.04 Central quadrant 25 8 17 ChT 16 64% 5 11 69%± 12 0.9 RT 9 36% 3 6 67%± 16 0.9 Medial quadrant 68 23 45 ChT 43 63% 14 29 67%± 7 n r 0.6 RT 25 37% 9 16 64%± 10 Table 6 — Five-year survival in patients with operable breast cancer and axillary lymph node metastases, without evidence of disease, treated either by ChT or RT, according to the site of tumor in the breast Opinions on the importance of postoperative irradiation in patients with oprable breast cancer are differing (4, 5, 6). Most authors believe that post-operative irradiation does not prolong the survival in patients with operable breast cancer and axillary lymph node metastases (4, 5, 15). Also, there has been no statistically significant difference in the survival of patients postoperatively irradiated on either a high-energy X-ray machine or Cobalt (16). Systemic ocult microme-tastases are often present at diagnosis of breast cancer, and therefore postoperative irradiation cannot prolong the survival in these patients. Still, it is possible that in some patients ocult micrometastases affect only locoregional lymph-nodes which are within the irradiation field. In such cases, postoperative irradiation could destroy these metastases, and subsequently result in a prolonged survival (17). However, untill now no such group of patients with locoregional lymph node involvement, in whom postoperative irradiation would be sensible, has been reported. Statistically insignificant differences i the survival of patients with tumors exceeding 2 cm or with more than 3 positive axillary lymph nodes are most probably due to the appearance of chemotherapy-resistant celi clones; on the other hand, a longer survival of some patients with postoperative irradiation whould also be considered as a possible cause of this. Patients with tumor in the lateral quadrant of the breast treated by adjuvant chemotherapy had statistically significantly longer survival without evidence of disease than the patients treated by postoperative irradiation. Perhaps, postoperative irradiation destroyed possible micrometastases in the parasternal lymph nodes, which are more likely to appear in tumors situated in the central quadrant than in those situated in the lateral quadrant (18). Possible difference in the survival between both adjuvanttreatment groups has disappeared owing to the prolonged survival of postoperatively irradiated patients with tumor in the medias-tinal or cental quadrant. Based on ther results of NSABP study on 1665 patients treated by radical mastectomy or radical mastectomy and postoperative irradiation, no difference in the survival according to the tumor site could be established (18, 19). There have been many reports published in the past few years on the results of postoperative clinical studies on adjuvant chemotherapy (1O, 11, 19, 20). In these studies the survival of patients with operable breast cancer and axillary lymph node metastases treated by radical mastectomy or radical mastectomy and adjuvant chemotherapy has been correlated. Their results are similar to ours. However, no statistically significant longer survival (16) has been established in premenopausal patients treated by adjuvant chemotherapy, for the difference with other authors. In our study the survivaly of patients treated by either postoperative irradiation or adjuvant chemotherapy have been correlated. The obtained results can be compared with those of other studies on adjuvant chemotherapy, considering that many studies comparing the survival of patients with radical mastectomy, and those with radical mastectomy and postoperative irradiation, has not established any statistically significant differences in the survival (2, 5, 15). Conclusion — Adjuvant systemic treatment has the potential of prolonging survival in some of the patients with operable breast cancer only. Every adjuvant treatment represents a severe strain on the patients. Therefore, it is of essential importance that the decision on adjuvant systemic treatment application is made only after the Radiol lugosl 1989; 23: 177-82 179 Stabuc B., et al.: Five-year survival of patients with breast cancer and axillary lymph node metastases treated by postoperative irradiation and .. relevant prognostic factors (i. e. the number of positive axillary lymph nodes, tumor size, grade of malignancy, menopausal status, hormone receptors) as well as patients's psychophysical condition have been carefully considered. Povzetek S-LETNO PREŽIVETJE BOLNIC Z RAKOM DOJKE IN POZITIVNIMI PAZDUŠNIMI BEZGAVKAMI ZDRAVLJENIH S POOPERATIVNIM OBSEVANJEM IN DOPOLNILNO SISTEMSKO KEMOTERAPIJO Avtor je ocenil S-letno preživetje bolnic z operabil-nim rakom dojke in zasevki v pazdušnih bezgavkah. Po modificirani radikalni mastektomiji (Maden-Patey) so bile bolnice zdravljene s pooperativnim obsevanjem ali dopolnilno sistemsko kemoterapijo po shemi CMF. Petletno preživejte 169 bolnic zdravljenih z dopolnilno sistemsko kemoterapijo je bilo 72%, 126 bolnic zdravljenih s pooperativnim obsevanjem pa 60% (p = 0,04). Petletno preživetje bolnic brez znamenj bolezni zdravljenih z dopolnilno sistemsko kemoterapijo je bilo 61 % in s pooperativnim obsevanjem 50% (p = 0,02). Statistično značilno daljše preživetje bolnic z dopolnilno sistemsko kemoterapijo (p < 0,05) je ugotovil le pri skupini bolnic s tumorjem od 2 cm ali manj kot tremi oziroma manj kot 7 pozitivnimi bezgavkami. Literatura 1. Incidenca raka v Slovenij 1984. Ljubljana: Onkološki inštitut — Register raka za SR Slovenijo, 1988. 2. Fisher B, Redmond C, Fisher ER etal. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985; 312: 674—81. 3. Veronesi U, Costa A. The role of surgery in the management of primary breast cancer. Clin Oncol 1982; 1: 853—73. 4. Stjernsward J. 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MD, The Institute of Oncology, Zaloška c. 2, 61000 Ljubljana 182 Radiol lugosl 1989: 23: 177-82